Tolerogenic dendritic cell-mediated regulatory T cell differentiation by Chinese herbal formulation attenuates colitis progression

  • J Adv Res. 2024 Apr 26:S2090-1232(24)00167-X. doi: 10.1016/j.jare.2024.04.023.
Chunhua Huang  1 ,  Cheng Lyu  2 ,  Heung-Lam Mok  2 ,  Yiqi Xu  2 ,  Ka-Wing Cheng  1 ,  Cheng Zhang  3 ,  Die Hu  1 ,  Lin Zhu  2 ,  Chengyuan Lin  2 ,  Xin Chen  4 ,  Hor-Yue Tan  5 ,  Zhaoxiang Bian  6
Affiliations
  • 1. Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China.
  • 2. Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong Special Administrative Region of China.
  • 3. School of Chinese Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of China.
  • 4. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Regions of China.
  • 5. Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China. Electronic address: [email protected].
  • 6. Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China. Electronic address: [email protected].
PMID: 38677546 DOI: 10.1016/j.jare.2024.04.023
Abstract

Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease characterized by loss of immune tolerance to luminal antigens and progressive intestinal tissue injury. Thus, the re-establishment of immune tolerance is crucial for suppressing aberrant immune responses and UC progression.

Objectives: This study aimed to investigate the mechanisms underlying the action of CDD-2103 and its bioactive compounds in mediating immune regulation in mouse models of colitis.

Methods: Two experimental colitis models, chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and T-cell transfer-induced Rag1-/- mice, were used to determine the effects of CDD-2103 on colitis progression. Single-cell transcriptome analysis was used to profile the immune landscape and its interactions after CDD-2103 treatment. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the major components interacting with lymphoid cells. A primary cell co-culture system was used to confirm the effects of bioactive component.

Results: CDD-2103 dose-dependently suppresses the progression of colitis induced by chemicals or T cell transplantation in Rag1-/- mice. The effect of CDD-2103 is primarily attributable to an increase in the de novo generation of regulatory T cells (Tregs) in the lamina propria (LP). Single-cell transcriptomic analysis revealed that CDD-2103 treatment increased the number of tolerogenic dendritic cells (DCs). Mechanistically, CDD-2103 promoted tolerogenic DCs accumulation and function by upregulating several genes in the electron transport chain related to Oxidative Phosphorylation, leading to increased differentiation of Tregs. Further LC-MS analysis identified several compounds in CDD-2103, particularly those distributed within the mesenteric lymph nodes of mice. Subsequent studies revealed that palmatine and berberine promoted tolerogenic bone marrow-derived dendritic cells (BMDC)-mediated Treg differentiation.

Conclusion: Overall, our study demonstrated that the clinically beneficial effect of CDD-2103 in the treatment of UC is based on the induction of immune tolerance. In addition, this study supports berberine and palmatine as potential chemical entities in CDD-2103 that modulate immune tolerance.

Keywords
CDD-2103; Chinese herbal formulation; Oxidative phosphorylation; Regulatory T cell; Tolerogenic dendritic cell; Ulcerative colitis.
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